| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The index knee must show evidence of chronic OA with a K-L grade of 1, 2, 3 or 4. Subjects who were screen failures for the United States (US) CNTX-4975i-OA-301 or CNTX-4975i-OA-304 trials may be considered for this trial if the K-L grade of the index knee is 1-4, inclusive. |
| Schmerzhafte Kniegelenksentzündung (Osteoarthritis) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Painful Osteoarthritis of the Knee |
| Schmerzhafte Entzündung im Knie |
|
| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10023476 |
| E.1.2 | Term | Knee osteoarthritis |
| E.1.2 | System Organ Class | 100000004859 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to determine the optimal procedures for administering CNTX-4975-05 as a single IA injection into knee(s) with OA, balancing comfort and ease of use of methods of cooling and administration. |
|
| E.2.2 | Secondary objectives of the trial |
• To describe the clinical benefit of CNTX-4975-05 treatment at Week 8 in a single knee with OA
• To describe the clinical benefit at Week 8 of treating bilateral knee OA with a single injection to each knee
• To describe the clinical benefit at Week 8 of treating a single knee with OA in subjects with partial joint replacement (PJR) or TJR in the contralateral knee
• To evaluate subject satisfaction (SS) with the overall benefit of CNTX-4975-05
• To evaluate SS with CNTX-4975-05 relative to SS with contralateral knee PJR or TJR
• To evaluate SS and investigator satisfaction (IS) with different treatment regimens
• To evaluate the responders to treatment through 8 weeks |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A subject will be eligible for study participation if the subject meets all of the following criteria:
1. Male or female subjects between 40 and 95 years of age (inclusive).
2. Confirmation of OA of the knee: radiography of both knees using standard standing films (scored by the investigator) or using the fixed flexion method, taken during the Screening Visit (prior radiographs of the knees of sufficient quality that have been taken within 2 years of the Screening Visit may be used for K-L grading). The index knee must show evidence of chronic OA with a K-L grade of 1, 2, 3 or 4. Subjects who were screen failures for the US CNTX-4975i-OA-301 or CNTX-4975i-OA-304 trials may be considered for this trial if the K-L grade of the index knee is 1-4, inclusive.
3. Confirmation of OA of the index knee: American College of Rheumatology (ACR) diagnostic criteria (ACR confirmation of bilateral knee OA for subjects who will have bilateral knee injections of CNTX-
4975-05).
4. For subjects for monoarticular knee injection, the index knee must have moderate to severe pain (≥5 and ≤9) at screening associated with OA, which must be stable for a minimum of 6 months prior to Screening, as assessed by the investigator. These subjects may have:
a) unilateral or bilateral OA, with the index knee having moderate to severe pain, and the contralateral knee having none to mild pain, OR
b) unilateral or bilateral OA, with the index knee having moderate to severe pain and the other knee having had a PJR or TJR within 5 years of the Screening Visit. The knee with the PJR/TJR is not to be injected with CNTX-4975-05.
For subjects for bilateral knee injection, the index knee must have moderate to severe pain (≥5 and ≤9) at screening associated with OA, and greater pain in the index knee than in the contralateral knee. Their pain must be stable for a minimum of 6 months prior to Screening, as assessed by the investigator. The index knee in these subjects is the one with the worst pain with walking. Where both knees have equal pain with walking, then the knee on the subject's dominant side will be
designated the index knee.
For qualifying knee pain with walking, subjects will use an NPRS (0-10; 0=no pain, 10=worst possible pain) to rate their knee pain with walking (both knees, except knees with PJR/TJR). The PJR/TJR pain should be rated using the NPRS scale, but will not be a qualifying pain score.
5. Body mass index ≤45 kg/m2.
6. Subjects must have failed 2 or more prior therapies. Failure is deemed to be inadequate relief in the opinion of the investigator. A therapy may be deemed to have been inadequate because of one or more of the following:
a) unacceptable AEs;
b) initial failure to achieve clinically adequate pain relief;
c) initial pain relief that was not maintained; and/or
d) medical condition resulting in contraindication to the standard of care appropriate to the severity of the index knee OA pain.
"Therapies" include, but are not limited to, the following: NSAIDs (including topical), opioids, duloxetine, other systemic therapy, IA corticosteroids, IA viscosupplements, physical therapy, bracing, and orthotics.
7. Females not of childbearing potential, defined as post-menopausal for at least 1 year, or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), or practicing one of the following medically acceptable methods of birth control throughout the study period:
• Hormonal methods such as oral, implantable, injectable, or transdermal contraceptives for a minimum of 1 full cycle (based on the subject's usual menstrual cycle period) before CNTX-4975-05
administration
• Total abstinence from sexual intercourse since the last menses before CNTX-4975-05 administration
• Intrauterine device
• Double barrier method (condoms, sponge, diaphragm, with spermicidal jellies or cream).
8. Able to speak, read, and understand the language of the study used for the informed consent.
9. Willing and able to:
a) understand the study requirements
b) abide by the study restrictions and requirements
c) complete the study procedures
d) be compliant and independently (i.e., without assistance) record responses on the efficacy scales during clinic visits
e) independently communicate meaningfully with the study personnel
10. Signed informed consent form (ICF) approved by the institutional review board (IRB)/independent ethics committee (IEC).
|
|
| E.4 | Principal exclusion criteria |
A subject will be excluded from the study if the subject meets any of the following criteria:
1. Joint replacement surgery of the index knee at any time, or open surgery of the index knee in the past 24 months. Joint replacement of the contralateral knee is permitted for subjects who will not receive an injection in the contralateral (natural) knee. For subjects with bilateral knee OA who will receive an injection into both knees, joint replacement surgery of both knees at any time, or open surgery of the index knee in the past 24 months, is excluded.
2. Prior arthroscopic surgery of the index knee within 6 months of Screening.
3. Any painful conditions of the index knee due to joint disease other than OA. For example, radicular or referred pain involving the index knee or from joint disease other than OA involving the index knee, such as, but not restricted to chondromalacia patellae, inflammatory diseases (e.g., rheumatoid arthritis, psoriatic arthritis), metabolic diseases, gout/pseudogout, hemochromatosis, acromegaly, etc.
4. Periarticular pain from any cause, including referred pain, bursitis, tendonitis, soft tissue tenderness, or subacute/acute pain from injury.
5. Other chronic pain anywhere in the body that requires the use of chronic analgesic medications, including, but not limited to, local painful areas, myofascial pain syndromes, fibromyalgia, genetic, metabolic abnormalities, hematologic, or neuropathic pain.
6. Instability of the index or contralateral knee (e.g., cruciate ligament tear or rupture, significant protruding meniscus, substantial ligamentous laxity, unstable PJR or TJR).
7. Misalignment (>10 degrees varus or valgus) of the index knee on standing.
8. Documented history of neuropathic arthropathy or finding of bony fragmentation in the index knee with imaging (radiographic, computed tomography, or magnetic resonance imaging).
9. Physical/occupational/chiropractic therapy for the lower extremities or acupuncture for the lower extremities within 15 days of Screening, or need for such therapy during the study.
10. Plans to have surgery, other invasive procedures, or IA injections (other than CNTX-4975-05) for either knee while participating in the study.
11. Current use of opioids for any condition other than for OA of the knees injected with CNTX-4975-05) (maximum dose of 15 mg of hydrocodone [or equivalent] per day).
12. Corticosteroid injection into the index or contralateral knee within 90 days of Screening.
13. Received IA viscosupplementation (e.g., Synvisc®, Hyalgan®) within 90 days of Screening.
14. History of allergic reaction to the planned local anesthesia/analgesic regimens, ethylenediaminetetraacetic acid, Kolliphor HS 15, butylated hydroxytoluene, or capsaicin.
15. Presence of any medical condition or unstable health status that, in the judgment of the investigator, might adversely impact the safety of the subject, or the conduct of the study, or negatively affect the resulting data, including chronic conditions that are likely to alter the rate of healing or are likely to result in safety complications unrelated to the study medication, or significantly compromise key organ systems.
For any question regarding eligibility, it is strongly recommended that the investigator discuss the subject with the medical monitor.
16. Is pregnant or is breast feeding.
17. Has a malignancy, a history of malignancy, or has received treatment for malignancy at any time, with exception of resected and cured basal cell carcinoma and squamous cell carcinoma of the skin.
18. Regular use of anticoagulant blood thinners (except low-dose aspirin, Dabigatran 150 mg once daily [qd], Enoxaparin 40 mg qd, Rivaroxaban 10 mg qd, or Apixaban 2.5 mg twice daily [bid], or clopidogrel 75 mg qd, which are allowed).
19. Active cutaneous disease at the anticipated site of CNTX-4975-05 injection that would prevent the safe administration of CNTX-4975-05.
20. Ulcer or open wound anywhere on the index knee.
21. Specific laboratory abnormalities:
• Hemoglobin <11.0 g/dL
• White blood cells <2.5 × 109/L
• Neutrophils <1.5 × 109/L
• Platelets <100 × 109/L
• Aspartate transaminase or alanine transaminase >2 × upper limit of normal
• Creatinine >1.6 mg/dL
• Glucose (fasting) >250 mg/dL
• Hemoglobin A1c (HgbA1c) >9.0%
22. Clinically significant abnormal laboratory result at the Screening Visit (in the opinion of the investigator), or significant organ disease that would put the subject at undue risk or affect the ability of the subject to participate in the trial. For any question regarding eligibility, it is strongly recommended that the investigator discusses the subject with the medical monitor.
23. Use of an investigational medication within 30 days of Screening or 5 pharmacokinetic or pharmacodynamic half-lives (whichever is longer), or scheduled to receive such an agent while participating in the current
study.
24. Prior participation in an ALGRX 4975 or CNTX-4975 study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is assessment of the CNTX-4975-05 treatment regimens, with the Breg Cooling Control Group as the standard, using a combination of 3 assessments of the index knee: 1) pain 30 minutes after CNTX-4975-05 injection (using the 0-4 scale of none, mild, moderate, moderately severe, and severe); 2) subject satisfaction with
the treatment regimen (SS); and 3) investigator satisfaction with the treatment regimen (IS). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• Assessment of the primary combined outcome using the contralateral knee for the subjects who received bilateral injections and the index knee for all other subjects • Assessment of the primary combined outcome for each subject type
• Assessment of the primary combined outcome, using the contralateral knee for the subjects who received bilateral injections
• Percent of Outcome Measures in Rheumatology-Osteoarthritis Research Society International (OMERACT-OARSI) responders at Week 8 for subjects with a single CNTX-4975-05 joint injection (index knee, moderate-to-severe pain; index knee, pain not >3 for contralateral knee)
• Percent of OMERACT-OARSI responders at Week 8 for subjects with bilateral knee injections of CNTX-4975-05 (index knee, moderate-tosevere pain index knee; both knees meeting OMERACT-OARSI responder criteria)
• Percent of OMERACT-OARSI responders at Week 8 for subjects with a single CNTX-4975-05 joint injection (population with index knee, moderate-to-severe pain index knee; non-index knee with PJR/TJR)
• For each of the 3 types of subjects, the absolute change; the number of subjects who have ≥30%, ≥50%, ≥70%, or ≥90% improvement area under the curve; and landmark analysis on the 5 subscales of the KOOS through Week 8 using the average of both knees:
o Pain
o Other symptoms
o Activities of daily living
o Sports and recreation
o Quality of life
Assess the SS of treatment with CNTX-4975-05 IA injection for each of the 3 types of subjects, and all subjects in the trial
• For subjects with a PJR/TJR, assess their satisfaction with the CNTX-4975-05 IA injection versus their satisfaction with their PJR/TJR |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 13 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 13 |
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